Methods for preparing dioranozinc compounds

ABSTRACT

There are provided methods for preparing diorganozinc compounds of formula R 2 Zn. For example, such a method can method comprise reacting together a compound of formula ZnX 2  with at least one compound chosen from compounds of formulas RM 1 T, R 2 M 1 , and RM 2 . R, X, M 1 , M 2 , and T can be various different chemical entities. Compounds of formula R 2 ZnR 3 , in which R 2  and R 3  are the same or different, can also prepared in a similar manner

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of InternationalPatent Application no. PCT/CA2008/000864 filed on May 6, 2008, whichclaims priority to U.S. Provisional Application No. 60/916,419 filed onMay 7, 2007. The above-mentioned applications are incorporated herein byreference in their entirety.

TECHNICAL FIELD

The present document relates to improvements in the field chemistry. Inparticular, it relates to a method for preparing diorganozinc compounds.

BACKGROUND OF THE DISCLOSURE

Finding the right balance between reactivity and selectivity is one ofthe greatest scientific challenges in modern chemistry. In this context,diorganozinc reagents have proven effective in asymmetriccatalysis.^([i]) Although, this family of organometallic reagents hasbeen known for years, the synthesis of functionalized diorganozinccompounds has, only recently, made some significant progress, beginningwith the seminal work of Knochel and co-workers.^([ii]) However, thesefunctionalized diorganozinc reagents are widely underused in asymmetriccatalysis, especially in non-academic laboratories. One explanation forthis observation is mainly that current methods for preparing them(Equations 1 to 3) are somewhat troublesome. One must deal with (1) thepotential hazards caused by the handling and distillation of highlypyrophoric chemicals and/or with (2) the presence of by-products, whichare sometimes in stoichiometric amount and incompatible with catalyticreactions.^([iii]) Depending on the synthetic method used, the mainby-products are either salts,^([iv]) residual organometallic speciessuch as boranes,^([v]) or simply an excess of reagent.^([vi]) Even ifsome diorganozinc compounds can be purified through simple distillationor sublimation, the approach remains tedious and limited to volatile andlow functionalized compounds.

R-Metal+ZnX₂→R₂Zn+Metal-X  (1)

R¹-Metal+ZnR² ₂→R¹ ₂Zn+Metal-R²  (2)

R¹-X+R² ₂Zn→R¹ ₂Zn+R²-X  (3)

SUMMARY OF THE DISCLOSURE

According to one aspect, there is provided a method for preparing acompound of formula (I):

R₂Zn  (I)

wherein

-   -   R is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₄-C₃₀ alkylsilylalkyl,        C₉-C₃₀ (alkyl)(aryl)silylalkyl, C₁₉-C₃₀ arylsilylalkyl, C₄-C₃₀        (alkyl)(heteroaryl)silylalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,        C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl,        C₂-C₂₀ carboxylic acid ester, C₃-C₂₀ carboxylic acid amide,        C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂ heterocyclyl,    -   the method comprising reacting a compound of formula (II) with        at least one compound chosen from compounds of formulas (IIIa),        (IIIb), and (IIIc):

ZnX₂  (II)

RM¹T  (IIIa)

R₂M¹  (IIIb)

RM²  (IIIc)

MOR⁶  (VI)

wherein

-   -   X is chosen from —OR¹, —SR¹, Cl, Br, I, C₂-C₂₀ alkylcarboxylate,        C₂-C₁₂ heteroarylcarboxylate, and C₆-C₂₀ arylcarboxylate, and        when X is Cl or Br, a compound of formula (VI) is further added;    -   R is as previously defined;    -   M is Na or K;    -   M¹ is Mg, Mn, Zr, Ti, or Ni;    -   M² is Li, or Na;    -   T is F, Cl, Br, I, OSO₂R, OR, CN, or OC(O)R;    -   R¹ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀        alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂        aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid        amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl, or    -   the two R¹ groups are linked together so as to form a 5 to 8        membered ring; and    -   R⁶ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀        alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂        aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid        amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl,        the alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl,        alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl,        (alkyl)(aryl)silylalkyl, arylsilylalkyl,        (alkyl)(heteroaryl)silylalkyl, alkenyl, alkynyl, alkylaryl,        arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid        amide, cycloalkyl, heteroaryl, and heterocyclyl, being        unsubstituted or substituted with at least one substituent which        is compatible with a diorganozinc compound. Such a substituent        can be chosen from a halogen (for example F, Cl, Br, or I) atom,        a deuterium atom, a tritium atom, —OH, —CN, —NO₂, —SH, —OR, —SR,        C₁-C₆ alkoxy, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₆        aminoalkyl, C₆-C₂₀ aralkyl, C₆-C₁₂ aryl, C₃-C₈ cycloalkyl,        C₁-C₁₂ heteroaryl, C₁-C₁₂ heterocyclyl, C₂-C₂₀ carboxylic acid        ester, C₃-C₂₀ carboxylic acid amide, C₁-C₆ hydroxyalkyl, C₂-C₃        cyclic acetal, C₁-C₁₂ acetal, C₁-C₁₂ acyclic orthoester, C₄-C₆        cyclic orthoester, C₁-C₁₂ sulfone, C₁-C₁₂ sulfoxide, C₂-C₁₂        carbamate, C₂-C₁₂ urea, C₂-C₁₂ sulfonamide, C₂-C₁₂ sulfoxamide,        C₂-C₁₂ phosphonate, C₂-C₁₂ phosphinoyl, C₂-C₁₂ hydroxamic acid        ester, and a suitable protecting group.

According to another aspect, there is provided a method for preparing acompound of formula (Ia):

R²ZnR³  (Ia)

wherein

-   -   R² and R³ are the same or different and they represent C₁-C₂₀        alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl, C₂-C₂₀ thioalkyl,        C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀ alkylthioalkyl,        C₂-C₂₀ alkylaminoalkyl, C₄-C₃₀ alkylsilylalkyl, C₉-C₃₀        (alkyl)(aryl)silylalkyl, C₁₉-C₃₀ arylsilylalkyl, C₄-C₃₀        (alkyl)(heteroaryl)silylalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,        C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl,        C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid amide,        C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or C₁-C₁₂ heterocyclyl,        the method comprising reacting a compound of formula (II) with        at least one compound chosen from compounds of formulas (IIId),        (IIIe), and (IIIf), and a least compound chosen from compounds        of formulas (IIIg), (IIIh), and (IIIi), or with a compound of        formula (IIIj):

ZnX₂  (II)

R²M¹T  (IIId)

(R²)_(s)M¹  (IIIe)

R²M²  (IIIf)

R³M¹T  (IIIg)

(R³)₂M¹  (IIIh)

R³M²  (IIIi)

R²M¹R³  (IIIj)

MOR⁶  (VI)

wherein

-   -   X is chosen from —OR¹, —SR¹, Cl, Br, I, C₂-C₂₀ alkylcarboxylate,        C₂-C₁₂ heteroarylcarboxylate, and C₆-C₂₀ arylcarboxylate and        when X is Cl or Br, a compound of formula (VI) is further added;    -   R² and R³ are as previously defined;    -   M is Na or K;    -   M¹ is Mg, Mn, Zr, Ti, or Ni;    -   M² is Li, or Na;    -   T is F, Cl, Br, I, OSO₂R², OR²CN, or OC(O)R²;    -   R¹ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀        alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂        aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid        amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl, or    -   the two R¹ groups are linked together so as to form a 5 to 8        membered ring; and    -   R⁶ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀        alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂        aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid        amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl,

the alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl,alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl,(alkyl)(aryl)silylalkyl, arylsilylalkyl, (alkyl)(heteroaryl)silylalkyl,alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acidester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl,being unsubstituted or substituted with at least one substituent whichis compatible with a diorganozinc compound. Such a substituent can bechosen from a halogen (for example F, Cl, Br, or I) atom, a deuteriumatom, a tritium atom, —OH, —CN, —NO₂, —SH, —OR, —SR, C₁-C₆ alkoxy, C₁-C₃alkyl, C₂-C₈ alkenyl, C₂-C₃ alkynyl, C₁-C₆ aminoalkyl, C₆-C₂₀ aralkyl,C₆-C₁₂ aryl, C₃-C₈ cycloalkyl, C₁-C₁₂ heteroaryl, C₁-C₁₂ heterocyclyl,C₂-C₂₀ carboxylic acid ester, C₃-C₂₀ carboxylic acid amide, C₁-C₆hydroxyalkyl, C₂-C₃ cyclic acetal, C₁-C₁₂ acetal, C₁-C₁₂ acyclicorthoester, C₄-C₆ cyclic orthoester, C₁-C₁₂ sulfone, C₁-C₁₂ sulfoxide,C₂-C₁₂ carbamate, C₂-C₁₂ urea, C₂-C₁₂ sulfonamide, C₂-C₁₂ sulfoxamide,C₂-C₁₂ phosphonate, C₂-C₁₂ phosphinoyl, C₂-C₁₂ hydroxamic acid ester,and a suitable protecting group.

According to another aspect, there is provided a method for preparing acompound of formula (Ia):

R²ZnR³  (Ia)

wherein

-   -   R² and R³ are the same or different and they represent a C₁-C₂₀        alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl, C₂-C₂₀ thioalkyl,        C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀ alkylthioalkyl,        C₂-C₂₀ alkylaminoalkyl, C₄-C₃₀ alkylsilylalkyl, C₉-C₃₀        (alkyl)(aryl)silylalkyl, C₁₉-C₃₀ arylsilylalkyl, C₄-C₃₀        (alkyl)(heteroaryl)silylalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,        C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl,        C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid amide,        C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂ heterocyclyl,

the method comprising reacting a compound of formula (IIa) with acompound of formula (IIIg), and a compound of formula (VI):

R²ZnX  (IIa)

R³M¹T  (IIIg)

MOR⁶  (VI)

wherein

-   -   X is chosen from —OR¹, —SR¹, Cl, Br, I, C₂-C₂₀ alkylcarboxylate,        C₂-C₁₂ heteroarylcarboxylate, and C₆-C₂₀ arylcarboxylate;    -   R² and R³ are as previously defined;    -   M¹ is Mg, Mn, Zr, Ti, or Ni;    -   M is Na or K;    -   T is F, Cl, Br, I, OSO₂R², OR, CN, or OC(O)R²;    -   R¹ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀        alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂        aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid        amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl; and    -   R⁶ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀        alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂        aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid        amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl,

the alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl,alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl,(alkyl)(aryl)silylalkyl, arylsilylalkyl, (alkyl)(heteroaryl)silylalkyl,alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acidester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl,being unsubstituted or substituted with at least one substituent whichis compatible with a diorganozinc compound. Such a substituent can bechosen from a halogen (for example F, Cl, Br, or I) atom, a deuteriumatom, a tritium atom, —OH, —CN, —NO₂, —SH, —OR, —SR, C₁-C₆ alkoxy, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₆ aminoalkyl, C₆-C₂₀ aralkyl,C₆-C₁₂ aryl, C₃-C₈ cycloalkyl, C₁-C₁₂ heteroaryl, C₁-C₁₂ heterocyclyl,C₂-C₂₀ carboxylic acid ester, C₃-C₂₀ carboxylic acid amide, C₁-C₆hydroxyalkyl, C₂-C₃ cyclic acetal, C₁-C₁₂ acetal, C₁-C₁₂ acyclicorthoester, C₄-C₆ cyclic orthoester, C₁-C₁₂ sulfone, C₁-C₁₂ sulfoxide,C₂-C₁₂ carbamate, C₂-C₁₂ urea, C₂-C₁₂ sulfonamide, C₂-C₁₂ sulfoxamide,C₂-C₁₂ phosphonate, C₂-C₁₂ phosphinoyl, C₂-C₁₂ hydroxamic acid ester,and a suitable protecting group.

According to another aspect, there is provided a method for preparing asubstantially salt-free diorganozinc compound of formula (I) or asubstantially salt-free composition comprising a diorganozinc compoundof formula (I) and at least one solvent:

R₂Zn  (I)

wherein

-   -   R is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C_(r) C₂₀ alkylaminoalkyl, C₄-C₃₀        alkylsilylalkyl, C₉-C₃₀ (alkyl)(aryl)silylalkyl, C₁₉-C₃₀        arylsilylalkyl, C₄-C₃₀ (alkyl)(heteroaryl)silylalkyl, C₂-C₂₀        alkenyl, C₂-C₂₀ alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀        arylalkyl, C₆-C₁₂ aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀        carboxylic acid amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or        a C₁-C₁₂ heterocyclyl,    -   the method comprising:        -   reacting a compound of formula (II) with at least one            compound chosen from compounds of formulas (IIIa), (IIIb),            and (IIIc) optionally in the presence of at least one            solvent so as to obtain an intermediate composition and            then, reacting a compound of formula (VI) with the            intermediate composition so as to obtain a mixture            comprising a solid phase and a liquid phase or at least two            solids;

ZnX₂  (II)

RM¹T  (IIIa)

R₂M¹  (IIIb)

RM²  (IIIc)

MOR⁶  (VI)

wherein

-   -   X is chosen from —OR¹, —SR¹, Cl, Br, I, C₂-C₂₀ alkylcarboxylate,        C₂-C₁₂ heteroarylcarboxylate, and C₆-C₂₀ arylcarboxylate;    -   R is as previously defined;    -   M is Na or K;    -   M¹ is Mg, Mn, Zr, Ti, or Ni;    -   M² is Li, or Na;    -   T is F, Cl, Br, I, OSO₂R, CN, OR or OC(O)R;    -   R¹ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀        alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂        aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid        amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl, or    -   the R¹ are linked together so as to form a 5 to 8 membered ring;        and    -   R⁶ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C_(r) C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl,        C₂-C₂₀ alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl,        C₆-C₁₂ aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic        acid amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl,    -   the alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl,        alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl,        (alkyl)(aryl)silylalkyl, arylsilylalkyl,        (alkyl)(heteroaryl)silylalkyl, alkenyl, alkynyl, alkylaryl,        arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid        amide, cycloalkyl, heteroaryl, and heterocyclyl, being        unsubstituted or substituted with at least one substituent        chosen from F, Cl, Br, I, a deuterium atom, a tritium atom, —OH,        —CN, —NO₂, —SH, —OR, —SR, C₁-C₆ alkoxy, C₁-C₈ alkyl, C₂-C₈        alkenyl, C₂-C_(g) alkynyl, C₁-C₆ aminoalkyl, C₆-C₂₀ aralkyl,        C₆-C₁₂ aryl, C₃-C_(a) cycloalkyl, C₁-C₁₂ heteroaryl, C₁-C₁₂        heterocyclyl, C₂-C₂₀ carboxylic acid ester, C₃-C₂₀ carboxylic        acid amide, C₁-C₆ hydroxyalkyl, C₂-C₃ cyclic acetal, C₁-C₁₂        acetal, C₁-C₁₂ acyclic orthoester, C₄-C₆ cyclic orthoester,        C₁-C₁₂ sulfone, C₁-C₁₂ sulfoxide, C₂-C₁₂ carbamate, C₂-C₁₂ urea,        C₂-C₁₂ sulfonamide, C₂-C₁₂ sulfoxamide, C₂-C₁₂ phosphonate,        C₂-C₁₂ phosphinoyl, C₂-C₁₂ hydroxamic acid ester, and a suitable        protecting group;        -   separating the solid phase and the liquid phase from one            another or separating the at least two solids from one            another; and        -   optionally substantially removing at least a portion of the            solvent from the liquid phase.

According to another aspect, there is provided a method for preparing asubstantially salt-free diorganozinc compound of formula (Ia) or asubstantially salt-free composition comprising a diorganozinc compoundof formula (Ia) and at least one solvent:

R²ZnR³  (Ia)

wherein

-   -   R² and R³ are the same or different and they represent C₁-C₂₀        alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl, C₂-C₂₀ thioalkyl,        C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀ alkylthioalkyl,        C₂-C₂₀ alkylaminoalkyl, C₄-C₃₀ alkylsilylalkyl, C₉-C₃₀        (alkyl)(aryl)silylalkyl, C₁₉-C₃₀ arylsilylalkyl, C₄-C₃₀        (alkyl)(heteroaryl)silylalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,        C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl,        C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid amide,        C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or C₁-C₁₂ heterocyclyl,

the method comprising:

-   -   reacting a compound of formula (II) with at least one compound        chosen from compounds of formulas (IIId), (IIIe), and (IIIf),        and a least compound chosen from compounds of formulas (IIIg),        (IIIh), and (IIIi), or with a compound of formula (IIIj),        optionally in the presence of at least one solvent so as to        obtain an intermediate composition and then, reacting a compound        of formula (VI) with the intermediate composition so as to        obtain a mixture comprising a solid phase and a liquid phase or        at least two solids;

ZnX₂  (II)

R²M¹T  (IIId)

(R²)₂M¹  (IIIe)

R²M²  (IIIf)

R³M¹T  (IIIg)

(R³)₂M¹  (IIIh)

R³M²  (IIIi)

R²M¹R³  (IIIj)

MOR⁶  (VI)

wherein

-   -   X is chosen from —OR¹, —SR¹, Cl, Br, I, C₂-C₂₀ alkylcarboxylate,        C₂-C₁₂ heteroarylcarboxylate, and C₆-C₂₀ arylcarboxylate;    -   R² and R³ are as previously defined;    -   M is Na or K;    -   M¹ is Mg, Mn, Zr, Ti, or Ni;    -   M² is Li, or Na;    -   T is F, Cl, Br, I, OSO₂R², OR²CN, or OC(O)R²;    -   R¹ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀        alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂        aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid        amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl, or    -   the two R¹ groups are linked together so as to form a 5 to 8        membered ring; and    -   R⁶ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀        alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂        aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid        amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl,    -   the alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl,        alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl,        (alkyl)(aryl)silylalkyl, arylsilylalkyl,        (alkyl)(heteroaryl)silylalkyl, alkenyl, alkynyl, alkylaryl,        arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid        amide, cycloalkyl, heteroaryl, and heterocyclyl, being        unsubstituted or substituted with at least one substituent which        is compatible with a diorganozinc compound. Such a substituent        can be chosen from a halogen (for example F, Cl, Br, or I) atom,        a deuterium atom, a tritium atom, —OH, —CN, —NO², —SH, —OR, —SR,        C₁-C₆ alkoxy, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₆        aminoalkyl, C₆-C₂₀ aralkyl, C₆-C₁₂ aryl, C₃-C₃ cycloalkyl,        C₁-C₁₂ heteroaryl, C₁-C₁₂ heterocyclyl, C₂-C₂₀ carboxylic acid        ester, C₃-C₂₀ carboxylic acid amide, C₁-C₆ hydroxyalkyl, C₂-C₃        cyclic acetal, C₁-C₁₂ acetal, C₁-C₁₂ acyclic orthoester, C₄-C₆        cyclic orthoester, C₁-C₁₂ sulfone, C₁-C₁₂ sulfoxide, C₂-C₁₂        carbamate, C₂-C₁₂ urea, C₂-C₁₂ sulfonamide, C₂-C₁₂ sulfoxamide,        C₂-C₁₂ phosphonate, C₂-C₁₂ phosphinoyl, C₂-C₁₂ hydroxamic acid        ester, and a suitable protecting group,        -   separating the solid phase and the liquid phase from one            another or separating the at least two solids from one            another; and        -   optionally substantially removing at least a portion of the            solvent from the liquid phase.

According to another aspect, there is provided a method for preparing asubstantially salt-free diorganozinc compound of formula (I) or asubstantially salt-free composition comprising a diorganozinc compoundof formula (I) and at least one solvent:

R₂Zn  (I)

wherein

-   -   R is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₄-C₃₀ alkylsilylalkyl,        C₉-C₃₀ (alkyl)(aryl)silylalkyl, C₁₉-C₃₀ arylsilylalkyl, C₄-C₃₀        (alkyl)(heteroaryl)silylalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,        C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl,        C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid amide,        C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂ heterocyclyl,

the method comprising:

-   -   reacting a composition comprising compound of formula (I) and a        compound of formula (VII) with a compound of formula (VI)        optionally in the presence of a solvent so as to obtain a        mixture comprising a solid phase and a liquid phase or at least        two solids;

MOR⁶  (VI)

M¹X₂  (VII)

wherein

-   -   X is chosen from —OR¹, —SR¹, Cl, Br, I, C₂-C₂₀ alkylcarboxylate,        C₂-C₁₂ heteroarylcarboxylate, and C₆-C₂₀ arylcarboxylate;    -   M is Na or K;    -   M¹ is Mg, Mn, Zr, Ti, or Ni;    -   R¹ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀        alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂        aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid        amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl, or    -   the R¹ are linked together so as to form a 5 to 8 membered ring;        and    -   R⁶ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C_(r) C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl,        C₂-C₂₀ alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl,        C₆-C₁₂ aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic        acid amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl,    -   the alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl,        alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl,        (alkyl)(aryl)silylalkyl, arylsilylalkyl,        (alkyl)(heteroaryl)silylalkyl, alkenyl, alkynyl, alkylaryl,        arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid        amide, cycloalkyl, heteroaryl, and heterocyclyl, being        unsubstituted or substituted with at least one substituent        chosen from F, Cl, Br, I, a deuterium atom, a tritium atom, —OH,        —CN, —NO₂, —SH, —OR, —SR, C₁-C₆ alkoxy, C₁-C₈ alkyl, C₂-C₈        alkenyl, C₂-C₈ alkynyl, C₁-C₆ aminoalkyl, C₆-C₂₀ aralkyl, C₆-C₁₂        aryl, C₃-C_(s) cycloalkyl, C₁-C₁₂ heteroaryl, C₁-C₁₂        heterocyclyl, C₂-C₂₀ carboxylic acid ester, C₃-C₂₀ carboxylic        acid amide, C₁-C₆ hydroxyalkyl, C₂-C₃ cyclic acetal, C₁-C₁₂        acetal, C₁-C₁₂ acyclic orthoester, C₄-C₆ cyclic orthoester,        C₁-C₁₂ sulfone, C₁-C₁₂ sulfoxide, C₂-C₁₂ carbamate, C₂-C₁₂ urea,        C₂-C₁₂ sulfonamide, C₂-C₁₂ sulfoxamide, C₂-C₁₂ phosphonate,        C₂-C₁₂ phosphinoyl, C₂-C₁₂ hydroxamic acid ester, and a suitable        protecting group;        -   separating the solid phase and the liquid phase from one            another or separating the at least two solids from one            another; and        -   optionally substantially removing at least a portion of the            solvent from the liquid phase.

According to another aspect, there is provided a method for preparing asubstantially salt-free diorganozinc compound of formula (Ia) or asubstantially salt-free composition comprising a diorganozinc compoundof formula (Ia) and at least one solvent:

R²ZnR³  (Ia)

wherein

-   -   R² and R³ are the same or different and they represent C₁-C₂₀        alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl, C₂-C₂₀ thioalkyl,        C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀ alkylthioalkyl,        C₂-C₂₀ alkylaminoalkyl, C₄-C₃₀ alkylsilylalkyl, C₉-C₃₀        (alkyl)(aryl)silylalkyl, C₁₉-C₃₀ arylsilylalkyl, C₄-C₃₀        (alkyl)(heteroaryl)silylalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,        C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl,        C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid amide,        C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or C₁-C₁₂ heterocyclyl,

the method comprising:

-   -   reacting a composition comprising at least one compound of        formula (Ia) and at least one compound of formula (VII) with a        compound of formula (VI) optionally in the presence of a solvent        so as to obtain a mixture comprising a solid phase and a liquid        phase or at least two solids;

MOR⁶  (VI)

M¹X₂  (VII)

wherein

-   -   X is chosen from —OR¹, —SR¹, Cl, Br, I, C₂-C₂₀ alkylcarboxylate,        C₂-C₁₂ heteroarylcarboxylate, and C₆-C₂₀ arylcarboxylate;    -   M is Na or K;    -   M¹ is Mg, Mn, Zr, Ti, or Ni;    -   R¹ is a C₁-C₂₀, alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀        alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂        aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid        amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl, or    -   the R¹ are linked together so as to form a 5 to 8 membered ring;        and    -   R⁶ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,        C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀        alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀        alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂        aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid        amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂        heterocyclyl,    -   the alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl,        alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl,        (alkyl)(aryl)silylalkyl, arylsilylalkyl,        (alkyl)(heteroaryl)silylalkyl, alkenyl, alkynyl, alkylaryl,        arylalkyl, aryl, acyl, carboxylic acid ester, carboxylic acid        amide, cycloalkyl, heteroaryl, and heterocyclyl, being        unsubstituted or substituted with at least one substituent        chosen from F, Cl, Br, I, a deuterium atom, a tritium atom, —OH,        —CN, —NO₂, —SH, —OR, —SR, C₁-C₆ alkoxy, C₁-C₈ alkyl, C₂-C₈        alkenyl, C₂-C₈ alkynyl, C₁-C₆ aminoalkyl, C₆-C₂₀ aralkyl, C₆-C₁₂        aryl, C₃-C_(s) cycloalkyl, C₁-C₁₂ heteroaryl, C₁-C₁₂        heterocyclyl, C₂-C₂₀ carboxylic acid ester, C₃-C₂₀ carboxylic        acid amide, C₁-C₆ hydroxyalkyl, C₂-C₃ cyclic acetal, C₁-C₁₂        acetal, C₁-C₁₂ acyclic orthoester, C₄-C₆ cyclic orthoester,        C₁-C₁₂ sulfone, C₁-C₁₂ sulfoxide, C₂-C₁₂ carbamate, C₂-C₁₂ urea,        C₂-C₁₂ sulfonamide, C₂-C₁₂ sulfoxamide, C₂-C₁₂ phosphonate,        C₂-C₁₂ phosphinoyl, C₂-C₁₂ hydroxamic acid ester, and a suitable        protecting group;        -   separating the solid phase and the liquid phase from one            another or separating the at least two solids from one            another; and        -   optionally substantially removing at least a portion of the            solvent from the liquid phase.

It was found that such methods can be applied to a wide scope ofreactions. It was also found that such a method is an efficient, safeand general method for preparing diorganozinc reagents while eliminatingsubstantially all by-products. Advantages such as the high reactivity ofcertain intermediates, for example organomagnesium reagents, theirreadily commercial availability and their ease of preparation andhandling, permits to easily employ them as main precursors fordiorganozinc reagents synthesis. These two methods can be used under thesame reaction conditions.

According to another aspect, there is provided a method for preparing acompound of formula (IV):

Zn(OR¹)₂  (IV)

wherein R¹ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl,C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₄-C₃₀ alkylsilylalkyl, C₉-C₃₀(alkyl)(aryl)silylalkyl, C₁₉-C₃₀ arylsilylalkyl, C₄-C₃₀(alkyl)(heteroaryl)silylalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₂-C₂₀acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl, C₂-C₂₀ carboxylicacid ester, C₁-C₂₀ carboxylic acid amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂heteroaryl, or a C₁-C₁₂ heterocyclyl, or

-   -   the two R¹ groups are linked together so as to form a 5 to 8        membered ring;

the alkyl, haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl,alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl,(alkyl)(aryl)silylalkyl, arylsilylalkyl, (alkyl)(heteroaryl)silylalkyl,alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acidester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl,being unsubstituted or substituted with at least one substituent chosenfrom a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, atritium atom, —OH, —CN, —NO₂, —SH, —OR, —SR, C₁-C₆ alkoxy, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₆ aminoalkyl, C₆-C₂₀ aralkyl, C₆-C₁₂aryl, C₃-C₈ cycloalkyl, C₁-C₁₂ heteroaryl, C₁-C₁₂ heterocyclyl, C₂-C₂₀carboxylic acid ester, C₃-C₂₀ carboxylic acid amide, C₁-C₆ hydroxyalkyl,C₂-C₃ cyclic acetal, C₁-C₁₂ acetal, C₁-C₁₂ acyclic orthoester, C₄-C₆cyclic orthoester, C₁-C₁₂ sulfone, C₁-C₁₂ sulfoxide, C₂-C₁₂ carbamate,C₂-C₁₂ urea, C₂-C₁₂ sulfonamide, C₂-C₁₂ sulfoxamide, C₂-C₁₂ phosphonate,C₂-C₁₂ phosphinoyl, C₂-C₁₂hydroxamic acid ester, and a suitableprotecting group,

-   -   the method comprising reacting a compound of formula (II) with a        compound of formula (V):

ZnX₂  (II)

MOR¹  (V)

wherein

-   -   X is Cl, Br or I;    -   M is Na or K; and    -   R¹ is as previously defined.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become more readily apparent fromthe following description of various embodiments as illustrated by wayof examples in the appended drawings wherein:

FIG. 1 is a picture taken during the preparation of Et₂Zn, wherein (A)represents Zn(OMe)₂ in diethylether, (B) represents a mixture ofZn(OMe)₂ in diethylether into which EtMgCl in diethylether has beenadded, and (C) represents the mixture shown in (B) after centrifugation,the liquid phase comprising Et₂Zn and diethylether and the solid phaseor precipitate comprising at least one magnesium salt chosen fromMg(OMe)₂, MgCl(OMe), MgCl₂, and mixtures thereof.

DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS

The expression “glyme-type solvent” as used herein can refer to varioussolvents. For example, a glyme-type solvent can be one of formulaR⁴O(CH₂CH₂O)_(n)R⁵ in which n is 1, 2, or 3, R⁴ and R⁵ are the same ordifferent and they represent a C₁-C₄ alkyl.

The term “alkyl” as used herein refers to a straight or branched alkyl.

The term “aryl” as used herein refers to a cyclic or polycyclic aromaticring.

The term “heteroaryl” as used herein refers to an aromatic cyclic orfused polycyclic ring system having at least one heteroatom selectedfrom the group consisting of N, O, and S. For example, the heteroarylgroup can be furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl,indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl,pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl,carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl,benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl,quinazolinyl, and so on.

The term “heterocyclyl” includes non-aromatic rings or ring systems thatcontain at least one ring having an at least one hetero atom (such asnitrogen, oxygen or sulfur). For example, this term can include all ofthe fully saturated and partially unsaturated derivatives of the abovementioned heteroaryl groups. Exemplary heterocyclic groups includepyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl,piperidinyl, piperazinyl, thiazolidinyl, isothiazolidinyl, andimidazolidinyl.

The term “cycloalkyl” as used herein refers to a hydrocarbon ring whichmay contain or not double bonds.

The expression “suitable protecting group” refers to any suitableprotecting group for a given group and described by Wuts, Peter G. M.,Greene Theodora W. in Greene's Protective Groups in Organic Synthesis,John Wiley & Sons, 4^(th) edition, December 2006, which is herebyincorporated by reference in its entirety. For example, the given groupcan be the hydroxy group of an hydroxyalkyl, the thiol group of athioalkyl, the amino group of an aminoalkyl, the alkyne group of analkynyl etc. Suitable protecting groups for an hydroxy group can be, forexample, silyls (such as trimethylsilyl (TMS), triethylsilyl (TES),t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS)).

The expression “substantially salt-free” when related to a diorganozinccompound or to a composition comprising a diorganozinc compound refers,for example, to a compound or a composition in which there is less thanabout 0.15 equivalent of salt per equivalent of diorganozinc. Forexample, such a compound or composition can comprise less than about0.1, 0.05, or 0.01 equivalent of salt per equivalent of diorganozinc.

When preparing a compound of formula (I) or (Ia) the reaction can becarried out in an organic solvent chosen from diethylether,t-butylmethylether, dibutylether, diphenylether, diisopropylether,dipropylether, dipentylether, dimethoxymethane, cyclopentylmethylether,diethoxymethane, derivatives thereof analogues thereof, and mixturesthereof. Alternatively, the organic solvent can be chosen fromglyme-type solvents. Another organic solvent can be further added to theorganic solvent. The other organic solvent being chosen from C₁-C₁₀hydrocarbons for example toluene, benzene, hexanes, pentane, andheptane.

The compound of formula (II) and the compound(s) of formula (s)(IIIa)-(IIIi) can be reacted together in the organic solvent andagitated. The same can also be applied to compounds of formulas (IIa),(IIIg) and (VI).

The compound of formula (II) can be reacted with the compounds offormulas (IIIa) (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh),(IIIi), (IIIj) by preparing a composition comprising the compound offormula (II) and the organic solvent, by adding the at least onecompound chosen from compounds of formulas (IIIa) (IIIb), (IIIc),(IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi) and (IIIj) to thecomposition so as to obtain a mixture, and by agitating the mixture. Thesame can also be applied to compounds of formulas (IIa), (IIIg) and(VI).

The compound of formula (II) can also be reacted with at least onecompound chosen from compounds of formulas (IIIa) (IIIb), (IIIc),(IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), and (IIIj) by preparinga composition comprising the compound of formula (II) and the organicsolvent, and by adding the at least one compound chosen from compoundsof formulas (IIIa) (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg),(IIIh), (IIIi), and (IIIj) dissolved in the organic solvent to thecomposition so as to obtain a mixture, and by agitating the mixture. Thesame can also be applied to compounds of formulas (IIa), (IIIg) and(VI).

When preparing a compound of formula (I) or (Ia), a precipitatecomprising at least one compound chosen from M¹X₂, M¹XT, M²X₂, and M²XTcan be formed. A liquid phase comprising the compound of formula (I) canbe at least partially separated from the precipitate. The mixtureso-obtained can be centrifuged or filtered so as to separate theprecipitate from the liquid phase comprising the compound of formula (I)or (Ia).

When preparing a compound of formula (Ia), a precipitate comprising acompound of formula TM¹OR¹ can be formed. The mixture so-obtained can becentrifuged or filtered so as to separate the precipitate from a liquidphase comprising the compound of formula (Ia).

The compound of formula (II) can be reacted with at least one compoundchosen from compounds of formulas (IIIa) (IIIb), (IIIc), (IIId), (IIIe),(IIIf), (IIIg), (IIIh), (IIIi), and (IIIj) at a temperature of about−20° C. to about 35° C. or a temperature of about 0° C. The reaction canbe carried out at a temperature of about 0° C. over a period of time ofat least 5 minutes and then a heterogeneous solution so obtained can beallowed to stir at room temperature for a period of at least 5 minutes.The same can also be applied to compounds of formulas (IIa), (IIIg) and(VI).

For example, when preparing a compound of formula (I), the compound offormula (II) can be reacted with at least one compound chosen fromcompounds of formulas (IIIa), (IIIb), and (IIIc) so as to obtain anintermediate composition and then, the compound of formula (VI) can bereacted with the intermediate composition.

For example, when preparing a compound of formula (Ia), the compound offormula (II) can be reacted with at least one compound chosen fromcompounds of formulas (IIId), (IIIe), and (IIIf), and at least onecompound chosen from compounds of formulas (IIIg), (IIIh), and (IIIi),or with a compound of formula (IIIj), so as to obtain an intermediatecomposition and then, the compound of formula (VI) can be reacted withthe intermediate composition.

For example, when preparing a compound of formula (Ia), the compound offormula (IIa) can be reacted with a compound of formulas (IIIg) so as toobtain an intermediate composition and then, the compound of formula(VI) can be reacted with the intermediate composition.

For example, compound of formula (IIa) can be reacted with the compoundof formula (IIIg) so as to obtain an intermediate composition and then,the compound of formula (VI) is reacted with the intermediatecomposition.

For example, compound of formula (IIa) can be reacted with the compoundof formula (VI) so as to obtain an intermediate composition and then,the compound of formula (IIIg) is reacted with the intermediatecomposition.

For example, the methods of the present disclosure can be carried out inthe presence or in the absence of a solvent. When carrying out a methodin the absence of solvent, the obtained product is a neat product. Whencarrying out a method in the presence of at least one solvent, acomposition comprising the desired compound and the at least one solventis obtained. Such a composition can be concentrated by evaporation,distillation, filtration membrane etc. Moreover, the solvent cansubstantially be removed from the composition in order to obtain thefinal product in a neat form.

For example, when a mixture comprising at least two solids is obtained,it is possible to separate the at least two solids (such as adiorganozinc and at least one salt) from one another. In fact, it ispossible, for example, to carry out a distillation or sublimation so asto selectively remove the diorganozinc compound from the rest of themixture. For example, the obtained diorganozinc can have a melting pointand/or a boiling point which is lower than the melting point and/orboiling point of the salts contained in the rest of the mixture.

For example, R, R² or R³ can be chosen from a C₁-C₁₂ alkyl, C₈-C₁₂arylalkyl, C₆-C₁₀ aryl, C₄-C₃₀ alkylsilylhydroxyalkyl and C₃-C₆cycloalkyl. Alternatively, R, R² or R³ is chosen from a C₂-C₁₀ alkyl,C₈-C₁₂ arylalkyl, benzyl, phenylethyl, phenyl, and C₅-C₆ cycloalkyl.

For example, X can be —OR¹ in which R¹ is a C₁-C₁₂ alkyl, C₂-C₁₂haloalkyl, C₃-C₁₂ alkoxyalkyl, C₁-C₁₂ alkylaminoalkyl, or C₂-C₁₂ acyl.Alternatively, X can be —OR¹ in which R¹ is RO(CH₂CH₂O)_(n)CH₂CH₂— inwhich R is as previously defined and n is 1, 2 or 3.

For example, X can be —OR¹ in which R¹ is CH₃—, n-C₅H₁₁, (CH₃)₂CH—,CH₃C(O)—, PhC(O)—, CF₃CH₂—, CH₃OCH₂CH₂—, CH₃OCH₂CH₂OCH₂CH₂—, or(CH₃)₂NCH₂CH₂—. Alternatively, X can be —OR¹ in which R¹ is —CH₃,n-C₅H₁₁, CH₃C(O)—, PhC(O)—, CF₃CH₂—, CH₃OCH₂CH₂—, CH₃OCH₂CH₂OCH₂CH₂—, or(CH₃)₂NCH₂CH₂—. X can also be is acetylacetonate. The compound offormula (II) can also be Zn(OCH₂CH₂O).

When preparing a compound of formula (I) R can be, for example, chosenfrom a C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₆-C₂₀ alkylaryl, and C₆-C₁₂aryl, X can be —OMe, and wherein the compound of formula (II) and atleast one compound of formula (IIIa), (IIIb) or (IIIc) can be reactedtogether in the presence of NaOMe. Alternatively, R can be for examplephenyl, X can be —OMe, and wherein the compound of formula (II) and theat least one compound of formula (IIIa), (IIIb) or (IIIc) can be reactedtogether in the presence of NaOMe.

For example, the compound of formula (II) can be reacted with a compoundof formula (IIIa) in which T is Cl, Br or I.

The method for preparing a compound of formula (I) or (Ia) can furthercomprise carrying out a nucleophilic addition on an organic substrate bycontacting the compound of formula (I) or (Ia) with the organicsubstrate in the presence or in the absence of a metal. The method canalso further comprise carrying out a nucleophilic addition on an organicsubstrate by contacting the compound of formula (I) or (Ia) with theorganic substrate in the presence of a metal and a ligand. For example,the metal can be Cu, Ti, Ni, or Zr. The nucleophilic addition can be acatalytic enantioselective addition. For example, the ligand can be achiral ligand chosen from Me-DuPHOS(O), morpholino isoborneol (MIB),dimethylaminoisoborneol (DAIB), other amino alcohol based ligands,Josiphos, binap, bis(phosphine), taddol, bis(oxazoline),phosphoramidites, phosphites, diamines, PHOX, Binap(O), Binaphtol, andpeptide based ligands. The nucleophilic addition can be carried out onan imine, an aldehyde, a ketone, or a β-nitroalkene of the organicsubstrate. The nucleophilic addition can also be a 1-4 addition carriedout on an α,β-unsaturated aldehyde or an α,β-unsaturated ketone.

The method for preparing a compound of formula (I) or (Ia) can furthercomprise carrying out a chemical reaction chosen from an oxidation of adiorganozinc into an alcohol, nucleophilic allylic substitution(S_(N)2′), a transition metal catalyzed cross-coupling (for examplenickel catalyzed cross-coupling or palladium catalyzed cross-coupling),a nucleophilic substitution (for example S_(N)2 on a ketal), anacylation, an anhydride opening, a carbozincation of an alkene or analkyne, an allylzincation of alkenylmetal/metalla-aza-claisen,preparation of organozinc or organozinc halides, a cyclopropanation andan epoxidation, by using the compound of formula (I) or (Ia).

When preparing a compound of formula (IV), a compound of formula (II)can be reacted with a compound of formula (V) in the presence of anorganic solvent chosen from diethylether, t-butylmethylether,dibutylether, diphenylether, diisopropylether, dipropylether,dipentylether, dimethoxymethane, cyclopentylmethylether,diethoxymethane, derivatives thereof, analogues thereof, and mixturesthereof. Alternatively, the organic solvent can be chosen fromglyme-type solvents. Another organic solvent can further be added to theorganic solvent. The other organic solvent can be chosen from C₁-C₁₀hydrocarbons such as toluene, benzene, hexanes, pentane, and heptane.For example, M can be Na and X can be Cl.

The compounds of formulas (V) and (VI) can be the same. For example,both can represent NaOR or KOR in which R is a C₁-C₁₀ alkyl.

The person skilled in the art would clearly recognize that the processesfor preparing compounds of formula (Ia) is similar to the process forpreparing compounds of formula (I). In fact, the particular embodimentsand examples previously mentioned concerning the process for preparingcompounds of formula (I), when possible, can all be applied to theprocesses for preparing compounds of formula (Ia).

The following examples represent in a non-limitative manner, variousembodiments.

Since the addition of a Grignard reagent on a zinc salt potentiallygenerates several organic, organometallic and inorganic species, some ofwhich are actually in equilibrium with each other^([vii]) and since itis difficult to accurately dose organometallic and inorganic impuritiesfound in diorganozinc solutions, several tests have been carried out byusing the prepared R₂Zn solution in the catalytic enantioselectiveaddition to imines.^([viii]) This reaction is known to be very sensitiveto the presence of salts.

TABLE 1 Zinc Salts Screening

Yield ee Entry X [%]^([a]) [%]^([b])  1 none^([c]) >95 0  2 Cl 51 27  3MeO 95 97  4 CF₃CH₂O 46 10  5 iPrO 83 0  6 CH₃OCH₂CH₂O 88 97  7CH₃OCH₂CH₂OCH₂CH₂O 65 88  8 (CH₃)₂NCH₂CH₂O 78 2  9 Acac 44 55 10 nC₅H₁₁O45 41 11 AcO 94 97 12 BzO 57 27 13 CH₂═CHCOO 45 89 14 OCH₂CH₂O 59 015^([d]) MeO 21 35 16^([e]) AcO >95 97 17^([e]) MeO 90 13 ^([a])NMRyields determined using an internal standard. ^([b])Enantiomericexcesses were determined by SFC on chiral stationary phase. ^([c])Nozinc salt was used. ^([d])3.95 equiv of EtMgBr in Et₂O was used.^([e])4.5 equiv of EtMgCl was used.

It was observed that the method for preparing diorganozinc istechnically simple, easy and fast. A simple manual or mechanicalstirring of the reaction during the preparation of the organozinccompounds can be made (see FIG. 1). Filtration or centrifugation canalso be used so as to led to a salt-free diorganozinc solution. Althoughsimilar results in terms of purity of the diorganozinc formed can beobtained using either technique, each offers certain advantages. Whilecentrifugation is quick and allows the simultaneous treatment of severalsamples, filtration, on the other hand, allows a better recovering ofthe solution and works well on a large scale.

Since Zn(OMe)₂ was not so far commercially available, it can be preparedfrom Et₂Zn and MeOH.^([ix]) To bridge this experimental gap, analternate convenient protocol was developed to generate this salt insitu (Equation 4). The latter was formed from ZnCl₂ and NaOMe (or KOMe).The resulting salt mixture can be used as a surrogate to pure Zn(OMe)₂and is suitable for the diorganozinc preparation.

When compared to the addition of neat Et₂Zn, the use of Zn(OMe)₂, eitherisolated or generated in situ, produced excellent yields andselectivities (Table 2, entries 1-3). In a similar fashion, the additionof more functionalized zinc salts was just as successful, suggestingthat their purity was equally excellent.

TABLE 2 Catalytic enantioselective addition to imines

Entry R Yield [%]^([a]) ee [%]^([b]) 1 Et 95 98 2 Et^([c]) 90 98 3Et^([d]) 96 98 4^([e]) n-C₁₀H₂₁ 73 97 5

n.d. n.d. 6 n-Bu 96 96 7 i-Pr 57 95 ^([a])Isolated yields.^([b])Enantiomeric excesses were determined by SFC on chiral stationaryphase. ^([c])Zn(OMe)₂ (2 equiv) was formed in situ from ZnCl₂ (2 equiv)and NaOMe (4.2 equiv). ^([d])Neat Et₂Zn was dissolved in Et₂O. ^([e])Thereaction was run for 48 h.

As it can be seen in Schemes 1 and 2, further examples of catalyticenantioselective addition to imines was made. In these two examples thereaction was carried out by preparing and using a mixed diorganozinc(R²ZnR³) and more particularly n-C₁₀H₂₁ZnCH₂TMS and BnZnMe.

To prove the generality of such a methodology, various enantioselectiveaddition systems were tested: the addition to β-nitroalkenes, tocyclohexenones and to aldehydes. Results obtained for the addition toβ-nitroalkenes ^([x]) turned out to be similar to the previous ones(Table 3).

TABLE 3 Catalytic enantioselective addition to β-nitroalkenes

Entry R Yield [%]^([a]) ee [%]^([b]) 1 Et 92 94 2 Et^([c]) 90 95 3Et^([d]) 92 95 4 n-C₁₀H₂₁ n.d. n.d. 5

n.d. n.d. ^([a])Isolated yields. ^([b])Enantiomeric excesses weredetermined by GC on chiral stationary phase. ^([c])Zn(OMe)₂ (2 equiv)was formed in situ from ZnCl₂ (2 equiv) and NaOMe (4.2 equiv). ZnBr₂ wasalso used instead of ZnCl₂ and similar results were obtained. ^([d])NeatEt₂Zn was dissolved in Et₂O.

The conjugated catalytic addition to cyclohexenone^([xi]) also proceededsmoothly with excellent reactivity. As the data indicate in Table 4, thesynthesis of dialkylzinc reagents from Zn(OMe)₂ tolerated primary,secondary, branched, linear or long chains. Furthermore, functionalitiesare well tolerated insofar as Grignard reagents themselves arecompatible with them.

TABLE 4 Catalytic enantioselective conjugated addition to cyclohexenone

Yield Entry R [%]^([a]) ee [%]^([b])  1 Et 89 >98^([f])  2 Et^([c]) 88>98^([f])  3 Et^([d]) 86 >98^([f])  4 Me n.d. n.d.  5 i-Pr >93 94  6n-Bu 94 >95  7 i-Bu 95 97  8 c-Hex 94 94  9 n-C₁₀H₂₁ 97 >98^([f])10^([e]) n-C₁₀H₂₁ n.d. n.d. 11 t-Bu 84, 19^([g]) 6, 27^([g]) 12PhCH₂CH₂— 97 >98^([f]) 13

n.d. n.d. ^([a])Isolated yield. ^([b])Enantiomeric excesses weredetermined by SFC on chiral stationary phase or by ¹³C NMR spectroscopyafter derivatization with 1,2-diphenyl ethylenediamine. ^([c])Zn(OMe)₂(2 equiv) was formed in situ from ZnCl₂ (2 equiv) and NaOMe (4.2 equiv).^([d])Neat R₂Zn was dissolved in Et₂O. ^([e])Zn(C₁₀H₂₁)₂ was generatedby hydroboration according to reference [3]. ^([f])The minor enantiomercould not be detected. ^([g])1.0 equivalent of styrene has been added.

Further study of the reactivity of dialkylzinc reagents prepared withthe method, reactions catalyzed by chiral amino alcohols have beentested.^([xii]) Once again, results of Table 5 showed that theenantioselective addition to aldehydes was very successful.

TABLE 5 Catalytic enantioselective addition to aldehydes

Entry R Yield [%]^([a]) ee [%]^([b]) 1 Et 93 98 2 Et^([c]) 95 98 3Et^([d]) 96 97 4 n-C₁₀H₂₁ 63^([e]) 97 5

n.d. n.d. ^([a])Isolated yields. ^([b])Enantiomeric excesses weredetermined by SFC on chiral stationary phase. ^([c])Zn(OMe)₂ (2 equiv)was formed in situ from ZnCl₂ (2 equiv) and NaOMe (4.2 equiv).^([d])Neat Et₂Zn was dissolved in Et₂O. ^([e])The low yield is explainedby the formation of the reduction product.

Moreover, the synthesis of mixed diorganozinc reagents was found to bevery simple: two different Grignard reagents can be added to Zn(OMe)₂(entries 4-5)^([xiii])

A further example of addition to an aldehyde is shown in Scheme 3. Inthis particular example, a mixed diorganozinc (R²ZnR³) was prepared andused.

Some other examples involving arylmagnesium reagents have also been madeas shown in Table 6.

TABLE 6 Modification using brominated Grignard reagents

Entry R Yield [%]^([a]) ee [%]^([b]) 1 Et 96 98 2 Et^([c]) 92 98 3 Ph 9098 4^([d],[e]) Ph 98 98 5^([d],[f]) Ph 63 98 6 TBDMSO(CH₂)₄ 70 98^([a])Isolated yield. ^([b])Enantiomeric excesses were determined by SFCon chiral stationary phase. ^([c])EtMgBr (3.3 equiv) was used incombination with NaOBz (0.6 equiv). ^([d])Mixed diorganozinc was used.^([d])EtZnPh was genereated from EtMgBr (1.5 equiv) and PhMgBr (1.45equiv). ^([e])EtZnPh was generated from Et₂Zn (0.75 equiv) and Ph₂Zn(0.75 equiv). ^([f])EtZnPh was generated from EtMgBr (1.5 equiv), PhMgBr(1.45 equiv), ZnCl₂ (1.5 equiv) and 1,4-dioxane (10.5 equiv) (seereference [xi]).

Since a slight excess of Zn(OMe)₂ can be, for example, used inproportion to two equivalents of the Grigrard reagent (i.e. 1.0equivalent of Zn(OMe)₂ for 1.95 equivalents of the Grignard reagent,which equals 1.02 equivalent of Zn(OMe)₂ for 2.0 equivalents of theGrignard reagent), traces of RZnOMe can still remain in the solution.However, such species are known to generate a stable tetramere, creatinglittle or no interactions with catalytic systems, as illustrated herein.When necessary, the use of an excess of Grignard reagent in combinationwith an insoluble and slow to react scavenger such as NaOBz,[xiv] willeliminate the presence of organozinc alkoxide (Table 6, entry 2).

Some other examples involving cyclohexylmagnesium chloride have alsobeen made as shown in Table 7.

TABLE 7 Other Examples using a Grignard reagent

Entry X Yield [%]^([a]) ee [%]^([b]) 1 OMe^([c]) 93 95 2 Cl 99 98 3Cl^([d]) 93 17 ^([a])GC yield or ¹H NMR yield. ^([b])Enantiomericexcesses were determined by GC on chiral stationary phase. ^([c])0equivalent of NaOMe was added. ^([d])Order of addition changed: NaOMeadded to ZnCl₂, then CyMgCl added.

Some examples of substantially salt-free diorganozinc compositions havebeen prepared.

TABLE 8 Preparation of substantially salt-free diorganozinc compounds

Entry R X Method of Separation Yield [%]^([a]) 1 Cy Cl Centrifugation57^([b]) 2 Cy Cl Filtration 92 ^([a])Yield obtained by titration withiodine. ^([b])Centrifuged solids not extracted to increase the yield.

In summary, the low solubility of magnesium salts such as magnesiummethoxide has been exploited in order to synthesize diorganozincreagents dissolved in a ethereal solvent (such as diethylether,t-butylmethylether, dibutylether, diphenylether, diisopropylether,dipropylether, dipentylether, dimethoxymethane, cyclopentylmethylether,diethoxymethane, derivatives or analogues thereof) without unwantedreaction by-products. It represents an attractive method to access bothhighly functionalized dialkylzinc and diarylzinc reagents. It alsopermits to easily prepare diorganozinc compounds. Finally, such a methodshows no change in the reactivity of all tested asymmetric catalyticreactions in comparison to purified reagents.

In Tables 1 to 8 and Schemes 1 to 3 the expression “Mg salts(s)” refersto a precipitate that comprises at least one magnesium salt chosen fromMg(OMe)₂, MgX(OMe), MgX₂, and mixtures thereof, wherein X is Cl, Br, orI in accordance with the type of Grignard reagent used i.e. chlorinated,brominated, or iodinated.

EXAMPLES

Typical experimental procedure: R₂Zn synthesis from Zn(OMe)₂ and RMgCl:To a test tube (18×100 mm) equipped with a magnetic stirrer (under argonatmosphere) charged with Zn(OMe)₂ (637 mg, 5 mmol) was added anhydrousEt₂O (5 mL) at room temperature. The heterogeneous solution was stirredfor 5-15 min and cooled to 0° C. for another 5-15 min. RMgCl 2M in Et₂O(9.75 mmol) was added dropwise with vigorous stirring over 5-10 min at0° C., and the heterogeneous solution was allowed to stir at roomtemperature for 1 h. The mixture was then centrifuged for 5-15 min (orfiltered) and the R₂Zn solution (4.5 M)^([xv],[xvi]) was gentlytransferred via cannula into an empty flame-dried flask purged withargon (or added to a reaction mixture via syringe). Results obtainedusing such a procedure can be found, for example, in Tables 2 to 5.

Typical experimental procedure: R₂Zn synthesis from ZnCl₂, NaOMe andRMgCl: To a test tube (18×100 mm) equipped with a magnetic stirrer(under argon atmosphere) charged with ZnCl₂ (682 mg, 5 mmol) and NaOMe(567 mg, 10.5 mmol) was added anhydrous Et₂O (5 mL) at room temperature(exothermic). The heterogeneous solution was stirred for 20 min andcooled to 0° C. for another 5-15 min. RMgCl 2M in Et₂O (9.75 mmol) wasadded dropwise with vigorous stirring over 5-10 min at 0° C., and theheterogeneous solution was allowed to stir at room temperature for 2 h.The mixture was then centrifuged for 5-15 min (or filtered) and the R₂Znsolution (≈0.5 M) was gently transferred via cannula into an emptyflame-dried flask purged with argon (or added to a reaction mixture viasyringe). Results obtained using such a procedure (using ZnCl₂ toprepare Zn(OMe)₂ in situ) can be found, for example, in some entries ofTables 2 to 5.

Another typical experimental procedure: R₂Zn synthesis from ZnCl₂, NaOMeand RMgCl: To a 100 mL flask equipped with a magnetic stirrer (underargon atmosphere) charged with ZnCl₂ (1.31 g, 9.6 mmol) was addedanhydrous Et₂O (10 mL) at room temperature. The heterogeneous solutionwas stirred for 2 hours and cooled to 0° C. for another 5-15 min. RMgCl2M in Et₂O (18.7 mmol) was added dropwise with vigorous stirring over 30min at 0° C., and the heterogeneous solution was allowed to stir at roomtemperature for 2 h. NaOMe (1.09 g, 20.2 mmol) was then added and themixture was stirred for 20 hours. The mixture was then centrifuged for10 min (or filtered) and the R₂Zn solution (≈0.4 M) was gentlytransferred via cannula into an empty flame-dried flask purged withargon (or added to a reaction mixture via syringe). Results obtainedusing such a procedure can be found, for example, in Table 7.

Typical experimental procedure with Zn(OMe)₂, NaOMe and RMgBr: To a testtube (18×100 mm) equipped with a magnetic stirrer (under argonatmosphere) charged with Zn(OMe)₂ (637 mg, 5 mmol) and NaOMe (650 mg, 12mmol) was added anhydrous Et₂O (5 mL) at room temperature. Theheterogeneous solution was stirred for 5-15 min and cooled to 0° C. foranother 5-15 min. RMgBr 2M in Et₂O (9.75 mmol) was added dropwise withvigorous stirring over 5-10 min at 0° C., and the heterogeneous solutionwas allowed to stir at room temperature for 2 h. The mixture was thencentrifuged for 5-15 min (or filtered) and the R₂Zn solution (≈0.5 M)was gently canulated in an empty flame-dried flask purged with argon (oradded to a reaction with a syringe). Results obtained using such aprocedure can be found, for example, in Table 6.

Typical experimental procedure with mixed diorganozinc compounds(R²ZnR³): To a test tube (18×100 mm) equipped with a magnetic stirrer(under argon atmosphere) charged with Zn(OMe)₂ (637 mg, 5 mmol) wasadded anhydrous Et₂O (5 mL) at room temperature. The heterogeneoussolution was stirred for 5-15 min and cooled to 0° C. for another 5-15min. R²MgCl 2M in Et₂O (5.00 mmol) was added dropwise with vigorousstirring over 5-10 min at 0° C., then R³MgCl 2M in Et₂O (4.75 mmol) wasadded dropwise with vigorous stirring over 5-10 min at 0° C. and theheterogeneous solution was allowed to stir at room temperature for 1 h.The mixture was then centrifuged for 5-15 min (or filtered) and theR²ZnR³ solution (≈0.5 M)^([xv]) was gently transferred via cannula intoan empty flame-dried flask purged with argon (or added to a reactionmixture via syringe). Results obtained using such a procedure can befound, for example, in Schemes 1 and 2 and in some entries of Table 6.

Typical experimental procedure for the preparation of substantiallysalt-free diorganozinc compounds: To a 100 mL flask equipped with amagnetic stirrer (under argon atmosphere) charged with a diorganozincsolution containing 2 equivalents of magnesium halide (9.6 mmol of R₂Znin 20 mL solvent such as diethylether, tert-butylmethylether,2-methyltetrahydrofuran, or diethoxymethane, was added NaOMe (1.09 g,20.2 mmol) and the mixture was stirred for 20 hours. The mixture wasthen centrifuged for 10 min (or filtered) and the R₂Zn solution M) wasgently transferred via cannula into an empty flame-dried flask purgedwith argon (or added to a reaction mixture via syringe). Obtention of asubstantially salt-free R₂Zn composition was proven indirectly by theenantioselective addition of R₂Zn to 2-cyclohexen-1-one, which gavesimilar results (>90% ee) to entries 1-2 found in table 7 (presence ofsalts lower considerably the enantioselectivity of addition, forexample, <50% ee). Results obtained in the preparation of asubstantially salt-free composition of diorganozinc using such aprocedure can be found, for example, in Table 8. It is possible toremove the solvent (for example by means of a distillation) so as toobtain the substantially salt-free diorganozinc compound in a neat form.It is also possible to concentrate the composition by removing at leasta portion of solvent (distillation, evaporation, filtration membranes,etc.)

Characterization

Other than exceptional cases, compounds in Tables 1 to 7 and Scheme 1were fully characterized (NMR ¹H and ¹³C, IR, mp, [α]_(D), MS, E.A,etc.). Exceptions are compounds obtained by addition of t-butyl andbenzyl (Table 4, entry 11; Scheme 2 and 3), for which only NMR ¹H andGC/SFC data are available. For known compounds, obtained data areconsistent with literature values.^(xvii,xviii). For new compounds(Table 2, entry 4; Scheme 1; Table 4, entry 9; Table 5, entry 4 andTable 6, entry 6) characterization values are consistent with proposedstructures and are reported hereafter.

Dicyclohexylzinc (as a 0.41 M solution in diethyl ether): Absence ofremaining alkylmagnesium reagent was confirmed by a negative Gilmantest.^(xix) Titer was determined by reaction with iodine dissolved inTHF (containing LiCl, 0.5M).^([xv]) The solution given after titrationwas dissolved in TBME and washed with 1M HCl, dried with Na₂SO₄ andanalysed by GC (area % of products): iodocyclohexane (89%), cyclohexane(6%), cyclohexanol (2%), cyclohexene (2%); Side products cyclohexanoland cyclohexene were not detected by ¹H and ¹³C NMR. ¹H NMR (400 MHz,1:1 v/v Cy₂Zn/Et₂O:C₆D₆) δ 0.96-1.06 (hidden under Et₂O signal,identified by HMQC; m, 2H_(H—C—Zn)), 1.32-1.50 (m, 6H), 1.55-1.64 (m,6H), 1.65-1.81 (m, 8H); Et₂O signals: 1.06 (t, J=7.2 Hz, 6H), 3.27 (q,J=7.2 Hz, 4H); cyclohexane signal: 1.36 (s, 12H, 14 mol % vs Cy₂Zn); ¹³CNMR (100 MHz, 1:1 v/v Cy₂Zn/Et₂O:C₆D₆) δ 28.27 (2CH₂), 31.05 (4CH₂),32.24 (4CH₂), 33.43 (2CH); Et₂O signals: 15.38 (2CH₃), 65.88 (2CH₂);cyclohexane signal: 27.22 (6CH₂); ¹H NMR (400 MHz, 1:1 v/vCy₂Zn/Et₂O:CDCl₃) δ 0.50-0.80 (hidden under Et₂O signal; m, 0.85-0.99(m, 6H), 1.05-1.14 (m, 6H), 1.15-1.25 (m, 4H), 1.26-1.35 (m, 4H); Et₂Osignals: 0.68 (t, J=7.2 Hz, 6H), 2.94 (q, J=7.2 Hz, 4H); cyclohexanesignal: 0.95 (s, 12H, 14 mol % vs Cy₂Zn); ¹³C NMR (100 MHz, 1:1 v/vCy₂Zn/Et₂O:CDCl₃) δ 27.24 (2CH₂), 30.00 (4CH₂), 31.39 (4CH₂), 32.28(2CH); Et₂O signals: 14.30 (2CH₃), 64.95 (2CH₂); cyclohexane signal:26.26 (6CH₂).

P,P-diphenyl-N-[(1S)-1-phenylundecyl]phosphinic amide: mp 95-96° C.;R_(f) 0.55 (10:90 hexane:EtOAc); [α]_(D) ²⁰ −6.0 (c 1.02, CHCl₃); ¹H NMR(400 MHz, CDCl₃) δ 0.88 (t, J=6.9 Hz, 2H), 1.05-1.37 (m, 8H), 1.75-1.87(m, 1H), 1.92-2.04 (m, 1H), 3.35 (dd, J=9.6, 6.5 Hz, 0H), 4.16 (qd,J=9.6, 6.5 Hz, 1H), 7.17 (dd, J=7.0, 1.3 Hz, 1H), 7.20-7.35 (m, 3H),7.37-7.51 (m, 2H), 7.76 (ddd, J=11.9, 8.2, 1.1 Hz, 1H), 7.87 (ddd,J=11.8, 8.1, 1.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.7, 22.3, 25.7,28.9, 29.0, 29.0, 29.2 (2C), 31.5, 39.4 (d, J_(C-P)=3.8 Hz), 55.5,126.1, 126.6, 127.8 (d, J_(C-P)=12.7 Hz), 128.0 (d, J_(C-P)=12.5 Hz),128.1, 131.2 (d, J_(C-P)=2.7 Hz), 131.4 (d, J_(C-P)=2.7 Hz), 131.5 (d,J_(C-P)=9.8 Hz), 132.2 (d, J_(C-P)=9.8 Hz), 131.8 (d, J_(C-P)=121.9 Hz),133.7 (d, J_(C-P=)120.7 Hz), 143.6 (d, J_(C-P)=6 Hz); ³¹P NMR (162 MHz,CDCl₃) δ 22.78; HRMS m/z (APCI+) calcd for C₂₉H₃₉N OP [M+H]⁺: 448.27693;found: 448.2770; IR (neat) 3147, 2923, 2853, 1457, 1438, 1197, 1181,1108, 1068, 932, 750, 720, 693, 605 cm⁻¹.

(3S)-3-decylcyclohexanone: R_(f) 0.51 (90:10 n-hexane:EtOAc); [α]_(D) ²⁰−12.1 (c 1.08, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 0.83 (t, J=6.9 Hz, 3H),1.13-1.35 (m, 19H), 1.52-1.65 (m, 1H), 1.71 (s, 1H), 1.80-1.89 (m, 1H),1.90-2.04 (m, 2H), 2.14-2.24 (m, 1H), 2.28 (dd, J=10.4, 7.0 Hz, 1H),2.33-2.40 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 14.1, 22.7, 25.4, 26.7,29.4, 29.7 (2C), 29.7, 29.8, 31.4, 32.0, 36.7, 39.2, 41.5, 48.3, 211.7;HRMS m/z (APCI+) calcd for C₁₆H₃₁O [M+H]⁺: 239.23694; found: 239.23696;IR (neat) 2922, 2852, 1714, 1465, 1345, 1313, 1224, 815, 722, 630 cm⁻¹.

(1S)-1-(2-naphthyl)-1-undecanol: mp 53-54° C.; R_(f) 0.35 (20:80EtOAc:hexane); [α]_(D) ²⁰ −23.0 (c 1.08 CHCl₃); ¹H NMR (400 Hz, CDCl₃) δ0.96 (t, J=6.8 Hz, 3H), 1.32 (s, 15H), 1.45 (d, J=8.7 Hz, 1H), 1.97-1.74(m, 2H), 2.46 (s, 1H), 4.81 (t, J=6.6 Hz, 1H), 7.57-7.46 (m, 3H), 7.77(s, 1H), 7.92-7.81 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 14.3, 22.9, 26.0,29.5, 29.7 (2C), 29.8 (2C), 32.1, 39.1, 74.9, 124.3, 124.8, 125.9,126.2, 127.8, 128.1, 128.3, 133.1, 133.4, 142.5; HRMS m/z (APCI+) calcdfor C₂₁H₃₀NaO [M+Na]⁺: 321.21888; found: 321.21787; IR (neat) 3273,3054, 2919, 2850, 1507, 1465, 1313, 1065, 1031, 896, 860, 826, 748 cm⁻¹.

(1S)-5-{[tert-butyl(dimethyl)silyl]oxy}-1-(2-naphthyl)-1-pentanol:R_(f)0.25 (20:80 EtOAc:hexane); [α]_(D) ²⁰ −19.5 (c 1.04 CHCl₃); ¹H NMR (400MHz, CDCl₃) δ 0.02 (s, 6H), 0.87 (s, 9H), 1.29-1.40 (m, 1H), 1.42-1.51(m, 1H), 1.55 (qn, J=6.9 Hz 2H), 1.75-1.94 (m, 2H), 2.17 (d, J=3.1 Hz,1H), 3.58 (t, J=6.4 Hz, 2H), 4.81 (td, J=6.7, 2.9 Hz, 1H), 7.40-7.51 (m,3H), 7.75 (s, 1H), 7.77-7.87 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ−5.1,18.5, 22.3, 26.2, 32.8, 38.9, 63.3, 74.9, 124.3, 124.8, 125.9, 126.3,127.9, 128.1, 128.4, 133.2, 133.5, 142.4; HRMS m/z (APCI+) calcd forC₂₁H₃₂NaO₂Si [M+Na]⁺: 367.20638; found: 367.20512; IR (neat) 3351, 3055,2928, 2856, 1602, 1508, 1471, 1462, 1387, 1360, 1254, 1096, 835, 775,746, 662 cm⁻¹.

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1. A method for preparing a compound of formula (I):R₂Zn  (I) wherein R is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀hydroxyalkyl, C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl,C₂-C₂₀ alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₄-C₃₀ alkylsilylalkyl,C₉-C₃₀ (alkyl)(aryl)silylalkyl, C₁₉-C₃₀ arylsilylalkyl, C₄-C₃₀(alkyl)(heteroaryl)silylalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₂-C₂₀acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl, C₂-C₂₀ carboxylicacid ester, C₁-C₂₀ carboxylic acid amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂heteroaryl, or a C₁-C₁₂ heterocyclyl, said method comprising reacting acompound of formula (II) with at least one compound chosen fromcompounds of formulas (IIIa), (IIIb), and (IIIc):ZnX₂  (II)RM¹T  (IIIa)R₂M¹  (IIIb)RM²  (IIIc)MOR⁶  (VI) wherein X is chosen from —OR¹, —SR¹, Cl, Br, C₂-C₂₀alkylcarboxylate, C₂-C₁₂ heteroarylcarboxylate, and C₆-C₂₀arylcarboxylate, and when X is Cl or Br, a compound of formula (VI) isfurther added; R is as previously defined; M is Na or K; M¹ is Mg; M² isLi, or Na; T is F, Cl, Br, I, OSO₂R, CN, OR or OC(O)R; R¹ is a C₁-C₂₀alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl, C₂-C₂₀ thioalkyl, C₂-C₂₀aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀ alkylthioalkyl, C₂-C₂₀alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₂-C₂₀ acyl, C₆-C₂₀alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl, C₂-C₂₀ carboxylic acid ester,C₁-C₂₀ carboxylic acid amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or aC₁-C₁₂ heterocyclyl, or said R¹ are linked together so as to form a 5 to8 membered ring; and R⁶ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀hydroxyalkyl, C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl,C₂-C₂₀ alkylthioalkyl, C_(r) C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl,C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid amide, C₃-C₁₂cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂ heterocyclyl, said alkyl,haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl,alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl,(alkyl)(aryl)silylalkyl, arylsilylalkyl, (alkyl)(heteroaryl)silylalkyl,alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acidester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl,being unsubstituted or substituted with at least one substituent chosenfrom F, Cl, Br, I, a deuterium atom, a tritium atom, —OH, —CN, —NO₂,—SH, —OR, —SR, C₁-C₆ alkoxy, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C_(g)alkynyl, C₁-C₆ aminoalkyl, C₆-C₂₀ aralkyl, C₆-C₁₂ aryl, C₃-C₈cycloalkyl, C₁-C₁₂ heteroaryl, C₁-C₁₂ heterocyclyl, C₂-C₂₀ carboxylicacid ester, C₃-C₂₀ carboxylic acid amide, C₁-C₆ hydroxyalkyl, C₂-C₃cyclic acetal, C₁-C₁₂ acetal, C₁-C₁₂ acyclic orthoester, C₄-C₆ cyclicorthoester, C₁-C₁₂ sulfone, C₁-C₁₂ sulfoxide, C₂-C₁₂ carbamate, C₂-C₁₂urea, C₂-C₁₂ sulfonamide, C₂-C₁₂ sulfoxamide, C₂-C₁₂ phosphonate, C₂-C₁₂phosphinoyl, C₂-C₁₂ hydroxamic acid ester, and a suitable protectinggroup.
 2. The method of claim 1, wherein R is a C₁-C₂₀ alkyl, C₁-C₂₀haloalkyl C₂-C₂₀ hydroxyalkyl, C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl,C₂-C₂₀ alkoxyalkyl, C₂-C₂₀ alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl,C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀arylalkyl, C₆-C₁₂ aryl, C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylicacid amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂heterocyclyl; and wherein said alkyl, haloalkyl, hydroxyalkyl,thioalkyl, aminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl,alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acidester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl,being unsubstituted or substituted with at least one substituent chosenfrom F, Cl, Br, I, a deuterium atom, a tritium atom, —OH, —CN, —NO₂,—SH, —OR, —SR, C₁-C₆ alkoxy, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₁-C₆ aminoalkyl, C₆-C₂₀ aralkyl, C₆-C₁₂ aryl, C₃-C₈ cycloalkyl, C₁-C₁₂heteroaryl, C₁-C₁₂ heterocyclyl, C₂-C₂₀ carboxylic acid ester, C₃-C₂₀carboxylic acid amide, C₁-C₆ hydroxyalkyl, C₂-C₃ cyclic acetal, C₁-C₁₂acetal, C₁-C₁₂ acyclic orthoester, C₄-C₆ cyclic orthoester, C₁-C₁₂sulfone, C₁-C₁₂ sulfoxide, C₂-C₁₂ carbamate, C₂-C₁₂ urea, C₂-C₁₂sulfonamide, C₂-C₁₂ sulfoxamide, C₂-C₁₂ phosphonate, C₂-C₁₂ phosphinoyl,and C₂-C₁₂ hydroxamic acid ester.
 3. The method of claim 1, wherein R ischosen from a C₁-C₁₂ alkyl, C₈-C₁₂ arylalkyl, C₆-C₁₀ aryl, and C₃-C₆cycloalkyl.
 4. The method of claim 1, wherein R is chosen from a C₂-C₁₀alkyl, benzyl, phenylethyl, phenyl, and cyclohexyl, and wherein ZnCl₂,ZnBr₂, or Zn(OMe)₂ is reacted with NaOMe so as to obtain an intermediatecomposition and then, said intermediate composition is reacted with atleast one of RMgCl, RMgBr, and RMgI.
 5. The method of claim 1, whereinsaid compound of formula (II) is reacted with said at least one compoundchosen from compounds of formulas (IIIa), (IIIb), and (IIIc), in thepresence of a solvent chosen from diethylether, t-butylmethylether,dibutylether, diphenylether, diisopropylether, dipropylether,dipentylether, dimethoxymethane, cyclopentylmethylether,diethoxymethane, a glyme-type solvent, analogues thereof, derivativesthereof, and mixtures thereof.
 6. The method of claim 5, wherein saidsolvent is diethylether.
 7. The method of claim 5, wherein said compoundof formula (II) is reacted with said at least one compound chosen fromcompounds of formulas (IIIa), (IIIb), and (IIIc) by preparing acomposition comprising said compound of formula (II) and said solvent,by adding said at least one compound chosen from compounds of formulas(IIIa), (IIIb), and (IIIc) to said composition so as to obtain amixture, and by agitating said mixture.
 8. The method of claim 5,wherein said compound of formula (II) is reacted with said at least onecompound chosen from compounds of formulas (IIIa), (Mb), and (IIIc) bypreparing a composition comprising said compound of formula (II) andsaid solvent, and by adding said at least one compound chosen fromcompounds of formulas (IIIa), (IIIb), and (IIIc) dissolved in saidsolvent to said composition so as to obtain a mixture, and by agitatingsaid mixture.
 9. The method of claim 1, wherein X is —OR¹ in which R¹ isa C₁-C₁₂ alkyl, C₂-C₁₂ haloalkyl, C₃-C₁₂ alkoxyalkyl, C₄-C₁₂alkylaminoalkyl, or C₂-C₁₂ acyl.
 10. The method of claim 9, whereinZn(OR¹)₂ is reacted with at least one of RMgCl, RMgBr, and RMgI.
 11. Themethod of claim 1, wherein Zn(OR¹)₂ is reacted with RMgCl in thepresence of in the presence of a solvent chosen from diethylether,t-butylmethylether, dibutylether, diphenylether, diisopropylether,dipropylether, dipentylether, dimethoxymethane, cyclopentylmethylether,diethoxymethane, a glyme-type solvent, analogues thereof, derivativesthereof, and mixtures thereof.
 12. The method of claim 10, whereinZn(OR¹)₂ is chosen from Zn(OMe)₂, Zn(OAc)₂, Zn(OCH₂CH₂OCH₃)₂, andZn(OCH₂CH₂OCH₂CH₂OCH₃)₂, Zn(OOCCH═CH₂).
 13. The method of claim 1,wherein ZnCl₂, or ZnBr₂ is reacted with at least one of RMgCl, RMgBr andRMgI, optionally in the presence of a solvent chosen from diethylether,t-butylmethylether, dibutylether, diphenylether, diisopropylether,dipropylether, dipentylether, dimethoxymethane, cyclopentylmethylether,diethoxymethane, a glyme-type solvent, analogues thereof, derivativesthereof, and mixtures thereof, so as to obtain an intermediatecomposition and then said compound of formula (VI) is reacted with saidintermediate composition.
 14. The method of claim 13, wherein R ischosen from a C₂-C₁₀ alkyl, benzyl, phenylethyl, phenyl, and cyclohexyl.15. The method of claim 1, wherein ZnCl₂ is reacted with RMgCl so as toobtain an intermediate composition and then, NaOMe is reacted with theintermediate composition.
 16. The method of claim 1, wherein R is chosena C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₆-C₂₀ alkylaryl, and C₆-C₁₂ aryl, Xis —OMe, and wherein said compound of formula (II) and said at least onecompound chosen from compounds of formulas (IIIa), (IIIb), and (IIIc)are reacted together in the presence of NaOMe.
 17. A method forpreparing a compound of formula (Ia):R²ZnR³  (Ia) wherein R² and R³ are the same or different and theyrepresent a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl, C₂-C₂₀thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀ alkylthioalkyl,C₂-C₂₀ alkylaminoalkyl, C₄-C₃₀ alkylsilylalkyl, C₉-C₃₀(alkyl)(aryl)silylalkyl, C₁₉-C₃₀ arylsilylalkyl, C₄-C₃₀(alkyl)(heteroaryl)silylalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₂-C₂₀acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl, C₂-C₂₀ carboxylicacid ester, C₁-C₂₀ carboxylic acid amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂heteroaryl, or a C₁-C₁₂ heterocyclyl, said method comprising reacting acompound of formula (IIa) with a compound of formula (IIIg), and acompound of formula (VI):R²ZnX  (IIa)R³M¹T  (IIIg)MOR⁶  (VI) wherein X is chosen from —OR¹, —SR¹, Cl, Br, C₂-C₂₀alkylcarboxylate, C₂-C₁₂ heteroarylcarboxylate, and C₆-C₂₀arylcarboxylate; R² and R³ are as previously defined; M¹ is Mg; M is Naor K; T is F, Cl, Br, I, OSO₂R², OR, CN, or OC(O)R²; R¹ is a C₁-C₂₀alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl, C₂-C₂₀ thioalkyl, C₂-C₂₀aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀ alkylthioalkyl, C₂-C₂₀alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₂-C₂₀ acyl, C₆-C₂₀alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl, C₂-C₂₀ carboxylic acid ester,C₁-C₂₀ carboxylic acid amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or aC₁-C₁₂ heterocyclyl; and R⁶ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀hydroxyalkyl, C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl,C₂-C₂₀ alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl,C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid amide, C₃-C₁₂cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂ heterocyclyl, said alkyl,haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl,alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl,(alkyl)(aryl)silylalkyl, arylsilylalkyl, (alkyl)(heteroaryl)silylalkyl,alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acidester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl,being unsubstituted or substituted with at least one substituent chosenfrom a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, atritium atom, —OH, —CN, —NO₂, —SH, —OR, —SR, C₁-C₆ alkoxy, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₆ aminoalkyl, C₆-C₂₀ aralkyl, C₆-C₁₂aryl, C₃-C_(g) cycloalkyl, C₁-C₁₂ heteroaryl, C₁-C₁₂ heterocyclyl,C₂-C₂₀ carboxylic acid ester, C₃-C₂₀ carboxylic acid amide, C₁-C₆hydroxyalkyl, C₂-C₃ cyclic acetal, C₁-C₁₂ acetal, C₁-C₁₂ acyclicorthoester, C₄-C₆ cyclic orthoester, C₁-C₁₂ sulfone, C₁-C₁₂ sulfoxide,C₂-C₁₂ carbamate, C₂-C₁₂ urea, C₂-C₁₂ sulfonamide, C₂-C₁₂ sulfoxamide,C₂-C₁₂ phosphonate, C₂-C₁₂ phosphinoyl, C₂-C₁₂ hydroxamic acid ester,and a suitable protecting group
 18. The method of claim 31, wherein saidcompound of formula (IIa) is reacted with said compound of formula(IIIg) so as to obtain an intermediate composition, and then saidcompound of formula (VI) is reacted with said intermediated composition,wherein R² and R³ are the same or different and they represent a C₁-C₂₀alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl, C₂-C₂₀ thioalkyl, C₂-C₂₀aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀ alkylthioalkyl, C₂-C₂₀alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₂-C₂₀ acyl, C₆-C₂₀alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl, C₂-C₂₀ carboxylic acid ester,C₁-C₂₀ carboxylic acid amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or aC₁-C₁₂ heterocyclyl; and wherein said alkyl, haloalkyl, hydroxyalkyl,thioalkyl, aminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl,alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acidester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl,being unsubstituted or substituted with at least one substituent chosenfrom a halogen (for example F, Cl, Br, or I) atom, a deuterium atom, atritium atom, —OH, —CN, —NO₂, —SH, —OR, —SR, C₁-C₆ alkoxy, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₆ aminoalkyl, C₆-C₂₀ aralkyl, C₆-C₁₂aryl, C₃-C₈ cycloalkyl, C₁-C₁₂ heteroaryl, C₁-C₁₂ heterocyclyl, C₂-C₂₀carboxylic acid ester, C₃-C₂₀ carboxylic acid amide, C₁-C₆ hydroxyalkyl,C₂-C₃ cyclic acetal, C₁-C₁₂ acetal, C₁-C₁₂ acyclic orthoester, C₄-C₆cyclic orthoester, C₁-C₁₂ sulfone, C₁-C₁₂ sulfoxide, C₂-C₁₂ carbamate,C₂-C₁₂ urea, C₂-C₁₂ sulfonamide, C₂-C₁₂ sulfoxamide, C₂-C₁₂ phosphonate,C₂-C₁₂ phosphinoyl, and C₂-C₁₂ hydroxamic acid ester.
 19. A method forpreparing a compound of formula (IV):Zn(OR¹)₂  (IV) wherein R¹ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀hydroxyalkyl, C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl,C₂-C₂₀ alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl,C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid amide, C₃-C₁₂cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂ heterocyclyl, or said R¹ arelinked together so as to form a 5 to 8 membered ring; said alkyl,haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl,alkylthioalkyl, alkylaminoalkyl, alkenyl, alkynyl, alkylaryl, arylalkyl,aryl, acyl, carboxylic acid ester, carboxylic acid amide, cycloalkyl,heteroaryl, and heterocyclyl, being unsubstituted or substituted with atleast one substituent chosen from a halogen (for example F, Cl, Br, orI) atom, a deuterium atom, a tritium atom, —OH, —CN, —NO₂, —SH, —OR,—SR, C₁-C₆ alkoxy, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₆aminoalkyl, C₆-C₂₀ aralkyl, C₆-C₁₂ aryl, C₃-C₈ cycloalkyl, C₁-C₁₂heteroaryl, C₁-C₁₂ heterocyclyl, C₂-C₂₀ carboxylic acid ester, C₃-C₂₀carboxylic acid amide, C₁-C₆ hydroxyalkyl, C₂-C₃ cyclic acetal, C₁-C₁₂acetal, C₁-C₁₂ acyclic orthoester, C₄-C₆ cyclic orthoester, C₁-C₁₂sulfone, C₁-C₁₂ sulfoxide, C₂-C₁₂ carbamate, C₂-C₁₂ urea, C₂-C₁₂sulfonamide, C₂-C₁₂ sulfoxamide, C₂-C₁₂ phosphonate, C₂-C₁₂ phosphinoyl,C₂-C₁₂ hydroxamic acid ester, and a suitable protecting group. saidmethod comprising reacting a compound of formula (II) with a compound offormula (V):ZnX₂  (II)MOR¹  (V) wherein X is Cl, or Br; M is Na or K; and R¹ is as previouslydefined, in the presence of an organic solvent chosen from diethylether,t-butylmethylether, dibutylether, diphenylether, diisopropylether,dipropylether, dipentylether, dimethoxymethane, cyclopentylmethylether,diethoxymethane, a glyme-type solvent, analogues thereof, derivativesthereof, and mixtures thereof.
 20. A method for preparing asubstantially salt-free diorganozinc compound of formula (I) or asubstantially salt-free composition comprising a diorganozinc compoundof formula (I) and at least one solvent:R₂Zn  (I) wherein R is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀hydroxyalkyl, C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl,C₂-C₂₀ alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₄-C₃₀ alkylsilylalkyl,C₉-C₃₀ (alkyl)(aryl)silylalkyl, C₁₉-C₃₀ arylsilylalkyl, C₄-C₃₀(alkyl)(heteroaryl)silylalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₂-C₂₀acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl, C₂-C₂₀ carboxylicacid ester, C₁-C₂₀ carboxylic acid amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂heteroaryl, or a C₁-C₁₂ heterocyclyl, said method comprising: reacting acomposition comprising compound of formula (I) and a compound of formula(VII), with a compound of formula (VI), optionally in the presence of asolvent, so as to obtain a mixture comprising a solid phase and a liquidphase or at least two solids;MOR⁶  (VI)M¹X₂  (VII) wherein X is chosen from —OR¹, —SR¹, Cl, Br, I, C₂-C₂₀alkylcarboxylate, C₂-C₁₂ heteroarylcarboxylate, and C₆-C₂₀arylcarboxylate; M is Na or K; M¹ is Mg, Mn, Zr, Ti, or Ni; R¹ is aC₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀ hydroxyalkyl, C₂-C₂₀ thioalkyl,C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl, C₂-C₂₀ alkylthioalkyl, C₂-C₂₀alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₂-C₂₀ acyl, C₆-C₂₀alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl, C₂-C₂₀ carboxylic acid ester,C₁-C₂₀ carboxylic acid amide, C₃-C₁₂ cycloalkyl, C₁-C₁₂ heteroaryl, or aC₁-C₁₂ heterocyclyl, or said R¹ are linked together so as to form a 5 to8 membered ring; and R⁶ is a C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl C₂-C₂₀hydroxyalkyl, C₂-C₂₀ thioalkyl, C₂-C₂₀ aminoalkyl, C₂-C₂₀ alkoxyalkyl,C₂-C₂₀ alkylthioalkyl, C₂-C₂₀ alkylaminoalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀alkynyl, C₂-C₂₀ acyl, C₆-C₂₀ alkylaryl, C₆-C₂₀ arylalkyl, C₆-C₁₂ aryl,C₂-C₂₀ carboxylic acid ester, C₁-C₂₀ carboxylic acid amide, C₃-C₁₂cycloalkyl, C₁-C₁₂ heteroaryl, or a C₁-C₁₂ heterocyclyl, said alkyl,haloalkyl, hydroxyalkyl, thioalkyl, aminoalkyl, alkoxyalkyl,alkylthioalkyl, alkylaminoalkyl, alkylsilylalkyl,(alkyl)(aryl)silylalkyl, arylsilylalkyl, (alkyl)(heteroaryl)silylalkyl,alkenyl, alkynyl, alkylaryl, arylalkyl, aryl, acyl, carboxylic acidester, carboxylic acid amide, cycloalkyl, heteroaryl, and heterocyclyl,being unsubstituted or substituted with at least one substituent chosenfrom F, Cl, Br, I, a deuterium atom, a tritium atom, —OH, —CN, —NO₂,—SH, —OR, —SR, C₁-C₆ alkoxy, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₁-C₆ aminoalkyl, C₆-C₂₀ aralkyl, C₆-C₁₂ aryl, C₃-C₈ cycloalkyl, C₁-C₁₂heteroaryl, C₁-C₁₂ heterocyclyl, C₂-C₂₀ carboxylic acid ester, C₃-C₂₀carboxylic acid amide, C₁-C₆ hydroxyalkyl, C₂-C₃ cyclic acetal, C₁-C₁₂acetal, C₁-C₁₂ acyclic orthoester, C₄-C₆ cyclic orthoester, C₁-C₁₂sulfone, C₁-C₁₂ sulfoxide, C₂-C₁₂ carbamate, C₂-C₁₂ urea, C₂-C₁₂sulfonamide, C₂-C₁₂ sulfoxamide, C₂-C₁₂ phosphonate, C₂-C₁₂ phosphinoyl,C₂-C₁₂ hydroxamic acid ester, and a suitable protecting group;separating said solid phase and said liquid phase from one another orseparating said at least two solids from one another; and optionallysubstantially removing at least a portion of said solvent from saidliquid phase.